miR-137 and its target T-type Ca_V 3.1 channel modulate dedifferentiation and proliferation of cerebrovascular smooth muscle cells in simulated microgravity rats by regulating calcineurin/NFAT pathway.

OBJECTIVES:Postflight orthostatic intolerance has been regarded as a major adverse effect after microgravity exposure, in which cerebrovascular adaptation plays a critical role. Our previous finding suggested that dedifferentiation of vascular smooth muscle cells (VSMCs) might be one of the key contributors to cerebrovascular adaptation under simulated microgravity. This study was aimed to confirm this concept and elucidate the underlying mechanisms. MATERIALS AND METHODS:Sprague Dawley rats were subjected to 28-day hindlimb-unloading to simulate microgravity exposure. VSMC dedifferentiation was evaluated by ultrastructural analysis and contractile/synthetic maker detection. The role of T-type Ca_V 3.1 channel was revealed by assessing its blocking effects. MiR-137 was identified as the upstream of Ca_V 3.1 channel by luciferase assay and investigated by gain/loss-of-function approaches. Calcineurin/nuclear factor of activated T lymphocytes (NFAT) pathway, the downstream of Ca_V 3.1 channel, was investigated by detecting calcineurin activity and NFAT nuclear translocation. RESULTS:Simulated microgravity induced the dedifferentiation and proliferation in rat cerebral VSMCs. T-type Ca_V 3.1 channel promoted the dedifferentiation and proliferation of VSMC. MiR-137 and calcineurin/NFATc3 pathway were the upstream and downstream signalling of T-type Ca_V 3.1 channel in modulating the dedifferentiation and proliferation of VSMCs, respectively. CONCLUSIONS:The present work demonstrated that miR-137 and its target T-type Ca_V 3.1 channel modulate the dedifferentiation and proliferation of rat cerebral VSMCs under simulated microgravity by regulating calcineurin/NFATc3 pathway.

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